Common variant approaches to study Mendelian disease gene function identify novel phenome and pathways associated with PLOD3

Background: The study of rare and common genetic disorders, in terms of study design, methods, and their genetic architecture, has largely been thought of as distinct. As sequencing technologies and analysis methods have advanced, we have learned that polygenic background can affect the penetrance, severity, and onset of certain Mendelian conditions. While genome-wide analyses have significantly contributed to our understanding of human disease, these studies rarely explore how common variation within a traditionally Mendelian disease genes affects phenotypic outcomes. Methods: In this study, we leverage common variant-based approaches and electronic health record (EHR)-derived phenome to study the phenotypic consequences associated with PLOD3, a Mendelian disease gene associated with BCARD syndrome. We conducted a gene-based phenome-wide association study (PheWAS) to identify phenotypes associated with reduced genetically predicted gene expression (GPGE) of PLOD3 in BioVU. To further quantify the phenotypic features associated with PLOD3, we leveraged a phenotype risk score (PheRS) constructed from the Mendelian features BCARD syndrome in OMIM and a PheRS constructed from our gene-based PheWAS. We used these PheRSs in a TWAS farmwork to expand genetic and pathway level associations. Results: We found that reduced GPGE of PLOD3 derived from common variants, can capture clinical phenome associated with Mendelian disease (BCARD syndrome) in addition to novel phenotypes not previously associated with PLOD3. These novel phenotypes were largely replicated in analyses of a protein quantitative trait loci (pQTL) for PLOD3 and in identity by descent (IBD) analysis of the PLOD3 locus. By generating PheRS for the Mendelian and gene-based phenome and using them in a TWAS framework, we identified novel genetic and pathway level associations. Conclusions: In this study, we present a scalable approach using EHR-based phenome and GPGE to identify novel phenome and use it as a tool for gene discovery to identify novel gene and pathway associations. This study leveraged biobank scale genetic and phenotype data to identify candidate phenotypes for expansion of the PLOD3 phenome and identify potential novel disease mechanisms. The application of these approaches to other Mendelian disease genes has the potential to aid in drug repurposing and identify candidate therapeutic targets.